RESUMEN
The hourglass model describes the convergence of species within the same phylum to a similar body plan during development; however, the molecular mechanisms underlying this phenomenon in mammals remain poorly described. Here, we compare rabbit and mouse time-resolved differentiation trajectories to revisit this model at single-cell resolution. We modeled gastrulation dynamics using hundreds of embryos sampled between gestation days 6.0 and 8.5 and compared the species using a framework for time-resolved single-cell differentiation-flows analysis. We find convergence toward similar cell-state compositions at E7.5, supported by the quantitatively conserved expression of 76 transcription factors, despite divergence in surrounding trophoblast and hypoblast signaling. However, we observed noticeable changes in specification timing of some lineages and divergence of primordial germ cell programs, which in the rabbit do not activate mesoderm genes. Comparative analysis of temporal differentiation models provides a basis for studying the evolution of gastrulation dynamics across mammals.
Asunto(s)
Gastrulación , Mesodermo , Animales , Conejos , Ratones , Gastrulación/genética , Mesodermo/fisiología , Diferenciación Celular/fisiología , Mamíferos/genética , Trofoblastos , Regulación del Desarrollo de la Expresión GénicaRESUMEN
In vitro cultured stem cells with distinct developmental capacities can contribute to embryonic or extraembryonic tissues after microinjection into pre-implantation mammalian embryos. However, whether cultured stem cells can independently give rise to entire gastrulating embryo-like structures with embryonic and extraembryonic compartments remains unknown. Here, we adapt a recently established platform for prolonged ex utero growth of natural embryos to generate mouse post-gastrulation synthetic whole embryo models (sEmbryos), with both embryonic and extraembryonic compartments, starting solely from naive ESCs. This was achieved by co-aggregating non-transduced ESCs, with naive ESCs transiently expressing Cdx2 or Gata4 to promote their priming toward trophectoderm and primitive endoderm lineages, respectively. sEmbryos adequately accomplish gastrulation, advance through key developmental milestones, and develop organ progenitors within complex extraembryonic compartments similar to E8.5 stage mouse embryos. Our findings highlight the plastic potential of naive pluripotent cells to self-organize and functionally reconstitute and model the entire mammalian embryo beyond gastrulation.
Asunto(s)
Células Madre Embrionarias , Gastrulación , Animales , Diferenciación Celular/fisiología , Embrión de Mamíferos/fisiología , Desarrollo Embrionario , Endodermo , Mamíferos , RatonesRESUMEN
Throughout development and aging, human cells accumulate mutations resulting in genomic mosaicism and genetic diversity at the cellular level. Mosaic mutations present in the gonads can affect both the individual and the offspring and subsequent generations. Here, we explore patterns and temporal stability of clonal mosaic mutations in male gonads by sequencing ejaculated sperm. Through 300× whole-genome sequencing of blood and sperm from healthy men, we find each ejaculate carries on average 33.3 ± 12.1 (mean ± SD) clonal mosaic variants, nearly all of which are detected in serial sampling, with the majority absent from sampled somal tissues. Their temporal stability and mutational signature suggest origins during embryonic development from a largely immutable stem cell niche. Clonal mosaicism likely contributes a transmissible, predicted pathogenic exonic variant for 1 in 15 men, representing a life-long threat of transmission for these individuals and a significant burden on human population health.
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Crecimiento y Desarrollo , Mosaicismo , Espermatozoides/metabolismo , Adolescente , Envejecimiento/sangre , Alelos , Células Clonales , Estudios de Cohortes , Humanos , Masculino , Modelos Biológicos , Mutación/genética , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
Single-cell RNA sequencing (scRNA-seq) provides a leap forward in resolving cellular diversity and developmental trajectories but fails to comprehensively delineate the spatial organization and precise cellular makeup of individual embryos. Here, we reconstruct from scRNA-seq and light sheet imaging data a canonical digital embryo that captures the genome-wide gene expression trajectory of every single cell at every cell division in the 18 lineages up to gastrulation in the ascidian Phallusia mammillata. By using high-coverage scRNA-seq, we devise a computational framework that stratifies single cells of individual embryos into cell types without prior knowledge. Unbiased transcriptome data analysis mapped each cell's physical position and lineage history, yielding the complete history of gene expression at the genome-wide level for every single cell in a developing embryo. A comparison of individual embryos reveals both extensive reproducibility between symmetric embryo sides and a large inter-embryonic variability due to small differences in embryogenesis timing.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Animales , Linaje de la Célula/genética , Cordados/genética , Biología Computacional/métodos , Gastrulación/genética , Regulación del Desarrollo de la Expresión Génica/genética , Reproducibilidad de los Resultados , Transcriptoma/genética , Urocordados/genéticaRESUMEN
Understanding human embryology has historically relied on comparative approaches using mammalian model organisms. With the advent of low-input methods to investigate genetic and epigenetic mechanisms and efficient techniques to assess gene function, we can now study the human embryo directly. These advances have transformed the investigation of early embryogenesis in nonrodent species, thereby providing a broader understanding of conserved and divergent mechanisms. Here, we present an overview of the major events in human preimplantation development and place them in the context of mammalian evolution by comparing these events in other eutherian and metatherian species. We describe the advances of studies on postimplantation development and discuss stem cell models that mimic postimplantation embryos. A comparative perspective highlights the importance of analyzing different organisms with molecular characterization and functional studies to reveal the principles of early development. This growing field has a fundamental impact in regenerative medicine and raises important ethical considerations.
Asunto(s)
Desarrollo Embrionario , Animales , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Humanos , Modelos Biológicos , Filogenia , Cigoto/metabolismoRESUMEN
Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large ß barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a ß propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the ß propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.
Asunto(s)
Toxinas Bacterianas/química , Proteínas de la Membrana/química , Proteínas del Tejido Nervioso/química , Sinapsis/metabolismo , Empalme Alternativo , Secuencias de Aminoácidos , Animales , Axones , Adhesión Celular , Línea Celular , AMP Cíclico/metabolismo , Femenino , Células HEK293 , Hormonas/química , Humanos , Insectos , Proteínas de la Membrana/metabolismo , Ratones , Conformación Molecular , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuropéptidos/química , Unión Proteica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Péptidos/química , Transducción de SeñalRESUMEN
Pseudouridylation (Ψ) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Ψ remains poorly understood. Here, we show that a Ψ-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Ψ "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF-mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Ψ in directing translation control in stem cells with important implications for development and disease.
Asunto(s)
Transferasas Intramoleculares/metabolismo , Biosíntesis de Proteínas , Seudouridina/metabolismo , ARN de Transferencia/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular , Diferenciación Celular , Factores Eucarióticos de Iniciación/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Humanos , Transferasas Intramoleculares/antagonistas & inhibidores , Transferasas Intramoleculares/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Síndromes Mielodisplásicos/patología , Conformación de Ácido Nucleico , Fosfoproteínas/metabolismo , Proteína I de Unión a Poli(A)/antagonistas & inhibidores , Proteína I de Unión a Poli(A)/genética , Proteína I de Unión a Poli(A)/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Nicho de Células MadreRESUMEN
Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
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Vida Libre de Gérmenes , Microbiota , Microglía/citología , Efectos Tardíos de la Exposición Prenatal/microbiología , Transcriptoma , Animales , Encéfalo/citología , Encéfalo/embriología , Encéfalo/metabolismo , Diferenciación Celular , Células Cultivadas , Ensamble y Desensamble de Cromatina , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Embarazo , Factores SexualesRESUMEN
Chromatin loops between gene pairs have been observed in diverse contexts in both flies and vertebrates. Combining high-resolution Capture-C, DNA fluorescence in situ hybridization, and genetic perturbations, we dissect the functional role of three loops between genes with related function during Drosophila embryogenesis. By mutating the loop anchor (but not the gene) or the gene (but not loop anchor), we disentangle loop formation and gene expression and show that the 3D proximity of paralogous gene loci supports their co-regulation. Breaking the loop leads to either an attenuation or enhancement of expression and perturbs their relative levels of expression and cross-regulation. Although many loops appear constitutive across embryogenesis, their function can change in different developmental contexts. Taken together, our results indicate that chromatin gene-gene loops act as architectural scaffolds that can be used in different ways in different contexts to fine-tune the coordinated expression of genes with related functions and sustain their cross-regulation.
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Cromatina , Cromosomas , Animales , Hibridación Fluorescente in Situ , Cromatina/genética , Drosophila/genéticaRESUMEN
Organismal development requires the reproducible unfolding of an ordered sequence of discrete steps (cell fate determination, migration, tissue folding, etc.) in both time and space. Here, we review the mechanisms that grant temporal specificity to developmental steps, including molecular clocks and timers. Individual timing mechanisms must be coordinated with each other to maintain the overall developmental sequence. However, phenotypic novelties can also arise through the modification of temporal patterns over the course of evolution. Two main types of variation in temporal patterning characterize interspecies differences in developmental time: allochrony, where the overall developmental sequence is either accelerated or slowed down while maintaining the relative duration of individual steps, and heterochrony, where the duration of specific developmental steps is altered relative to the rest. New advances in in vitro modeling of mammalian development using stem cells have recently enabled the revival of mechanistic studies of allochrony and heterochrony. In both cases, differences in the rate of basic cellular functions such as splicing, translation, protein degradation, and metabolism seem to underlie differences in developmental time. In the coming years, these studies should identify the genetic differences that drive divergence in developmental time between species.
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Evolución Biológica , Mamíferos , Animales , Embrión de Mamíferos , Diferenciación Celular/genéticaRESUMEN
Multiple division cycles without growth are a characteristic feature of early embryogenesis. The female germline loads proteins and RNAs into oocytes to support these divisions, which lack many quality control mechanisms operating in somatic cells undergoing growth. Here, we describe a small RNA-Argonaute pathway that ensures early embryonic divisions in C. elegans by employing catalytic slicing activity to broadly tune, instead of silence, germline gene expression. Misregulation of one target, a kinesin-13 microtubule depolymerase, underlies a major phenotype associated with pathway loss. Tuning of target transcript levels is guided by the density of homologous small RNAs, whose generation must ultimately be related to target sequence. Thus, the tuning action of a small RNA-catalytic Argonaute pathway generates oocytes capable of supporting embryogenesis. We speculate that the specialized nature of germline chromatin led to the emergence of small RNA-catalytic Argonaute pathways in the female germline as a post-transcriptional control layer to optimize oocyte composition.
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Caenorhabditis elegans/embriología , Caenorhabditis elegans/metabolismo , Embrión no Mamífero/metabolismo , Redes y Vías Metabólicas , Oocitos/metabolismo , Animales , Proteínas Argonautas/metabolismo , Secuencia de Bases , Caenorhabditis elegans/citología , Proteínas de Caenorhabditis elegans/metabolismo , División Celular , Embrión no Mamífero/citología , Desarrollo Embrionario , Femenino , Cinesinas/metabolismo , Microtúbulos/metabolismo , Datos de Secuencia Molecular , Procesamiento Postranscripcional del ARNRESUMEN
Land plants can grow to tremendous body sizes, yet even the most complex architectures are the result of iterations of the same developmental processes: organ initiation, growth, and pattern formation. A central question in plant biology is how these processes are regulated and coordinated to allow for the formation of ordered, 3D structures. All these elementary processes first occur in early embryogenesis, during which, from a fertilized egg cell, precursors for all major tissues and stem cells are initiated, followed by tissue growth and patterning. Here we discuss recent progress in our understanding of this phase of plant life. We consider the cellular basis for multicellular development in 3D and focus on the genetic regulatory mechanisms that direct specific steps during early embryogenesis.
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Morfogénesis , Semillas/embriología , Tipificación del Cuerpo , Nicho de Células MadreRESUMEN
Eukaryotic cells regulate 5'-triphosphorylated RNAs (ppp-RNAs) to promote cellular functions and prevent recognition by antiviral RNA sensors. For example, RNA capping enzymes possess triphosphatase domains that remove the γ phosphates of ppp-RNAs during RNA capping. Members of the closely related PIR-1 (phosphatase that interacts with RNA and ribonucleoprotein particle 1) family of RNA polyphosphatases remove both the ß and γ phosphates from ppp-RNAs. Here, we show that C. elegans PIR-1 dephosphorylates ppp-RNAs made by cellular RNA-dependent RNA polymerases (RdRPs) and is required for the maturation of 26G-RNAs, Dicer-dependent small RNAs that regulate thousands of genes during spermatogenesis and embryogenesis. PIR-1 also regulates the CSR-1 22G-RNA pathway and has critical functions in both somatic and germline development. Our findings suggest that PIR-1 modulates both Dicer-dependent and Dicer-independent Argonaute pathways and provide insight into how cells and viruses use a conserved RNA phosphatase to regulate and respond to ppp-RNA species.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimología , Monoéster Fosfórico Hidrolasas/metabolismo , Procesamiento Postranscripcional del ARN , ARN/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Regulación del Desarrollo de la Expresión Génica , Monoéster Fosfórico Hidrolasas/genética , Fosforilación , ARN/genética , Caperuzas de ARN , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/metabolismo , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Espermatogénesis , Especificidad por SustratoRESUMEN
Epigenetic reprogramming occurs during gametogenesis as well as during embryogenesis to reset the genome for early development. In flowering plants, many heterochromatic marks are maintained in sperm, but asymmetric DNA methylation is mostly lost. Asymmetric DNA methylation is dependent on small RNA but the re-establishment of silencing in embryo is not well understood. Here we demonstrate that small RNAs direct the histone H3 lysine 9 dimethylation during Arabidopsis thaliana embryonic development, together with asymmetric DNA methylation. This de novo silencing mechanism depends on the catalytic domain of SUVH9, a Su(Var)3-9 homolog thought to be catalytically inactive.
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Arabidopsis/genética , Arabidopsis/metabolismo , Metilación de ADN/genética , Histonas/metabolismo , ARN de Planta/metabolismo , Semillas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Epigénesis Genética/genética , Silenciador del Gen , Semillas/genéticaRESUMEN
Constitutive heterochromatin is essential for transcriptional silencing and genome integrity. The establishment of constitutive heterochromatin in early embryos and its role in early fruitfly development are unknown. Lysine 9 trimethylation of histone H3 (H3K9me3) and recruitment of its epigenetic reader, heterochromatin protein 1a (HP1a), are hallmarks of constitutive heterochromatin. Here, we show that H3K9me3 is transmitted from the maternal germline to the next generation. Maternally inherited H3K9me3, and the histone methyltransferases (HMT) depositing it, are required for the organization of constitutive heterochromatin: early embryos lacking H3K9 methylation display de-condensation of pericentromeric regions, centromere-centromere de-clustering, mitotic defects, and nuclear shape irregularities, resulting in embryo lethality. Unexpectedly, quantitative CUT&Tag and 4D microscopy measurements of HP1a coupled with biophysical modeling revealed that H3K9me2/3 is largely dispensable for HP1a recruitment. Instead, the main function of H3K9me2/3 at this developmental stage is to drive HP1a clustering and subsequent heterochromatin compaction. Our results show that HP1a binding to constitutive heterochromatin in the absence of H3K9me2/3 is not sufficient to promote proper embryo development and heterochromatin formation. The loss of H3K9 HMTs and H3K9 methylation alters genome organization and hinders embryonic development.
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Proteínas Cromosómicas no Histona , Heterocromatina , Histonas , Animales , Histonas/metabolismo , Histonas/genética , Heterocromatina/metabolismo , Heterocromatina/genética , Metilación , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Homólogo de la Proteína Chromobox 5 , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Embrión no Mamífero/metabolismo , Genoma de los Insectos , Desarrollo Embrionario/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genéticaRESUMEN
Out of many intracellular bacteria, only the mitochondria and chloroplasts abandoned their independence billions of years ago and became endosymbionts within the host eukaryotic cell. Consequently, one cannot grow eukaryotic cells without their mitochondria, and the mitochondria cannot divide outside of the cell, thus reflecting interdependence. Here, we argue that such interdependence underlies the fundamental role of mitochondrial activities in the emergence of metazoans. Several lines of evidence support our hypothesis: (a) Differentiation and embryogenesis rely on mitochondrial function; (b) mitochondrial metabolites are primary precursors for epigenetic modifications (such as methyl and acetyl), which are critical for chromatin remodeling and gene expression, particularly during differentiation and embryogenesis; and (c) mitonuclear coregulation adapted to accommodate both housekeeping and tissue-dependent metabolic needs. We discuss the evolution of the unique mitochondrial genetic system, mitochondrial metabolites, mitonuclear coregulation, and their critical roles in the emergence of metazoans and in human disorders.
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Genoma/genética , Mitocondrias/genética , Animales , Cromatina/genética , Desarrollo Embrionario/genética , Epigénesis Genética/genética , HumanosRESUMEN
Embryogenesis depends on a highly coordinated cascade of genetically encoded events. In animals, maternal factors contributed by the egg cytoplasm initially control development, whereas the zygotic nuclear genome is quiescent. Subsequently, the genome is activated, embryonic gene products are mobilized, and maternal factors are cleared. This transfer of developmental control is called the maternal-to-zygotic transition (MZT). In this review, we discuss recent advances toward understanding the scope, timing, and mechanisms that underlie zygotic genome activation at the MZT in animals. We describe high-throughput techniques to measure the embryonic transcriptome and explore how regulation of the cell cycle, chromatin, and transcription factors together elicits specific patterns of embryonic gene expression. Finally, we illustrate the interplay between zygotic transcription and maternal clearance and show how these two activities combine to reprogram two terminally differentiated gametes into a totipotent embryo.
Asunto(s)
Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , ARN Mensajero Almacenado/genética , Transcripción Genética , Cigoto/metabolismo , Animales , Ciclo Celular , Cromatina/genética , Cromatina/ultraestructura , Proteínas de Drosophila/fisiología , Proteínas del Huevo/genética , Embrión no Mamífero , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento , Histonas/fisiología , Humanos , Modelos Genéticos , Oocitos/metabolismo , Embarazo , Estabilidad del ARN , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacos , Transcriptoma , Proteínas de Xenopus/fisiología , Proteínas de Pez Cebra/fisiologíaRESUMEN
Current models suggest that chromosome domains segregate into either an active (A) or inactive (B) compartment. B-compartment chromatin is physically separated from the A compartment and compacted by the nuclear lamina. To examine these models in the developmental context of C. elegans embryogenesis, we undertook chromosome tracing to map the trajectories of entire autosomes. Early embryonic chromosomes organized into an unconventional barbell-like configuration, with two densely folded B compartments separated by a central A compartment. Upon gastrulation, this conformation matured into conventional A/B compartments. We used unsupervised clustering to uncover subpopulations with differing folding properties and variable positioning of compartment boundaries. These conformations relied on tethering to the lamina to stretch the chromosome; detachment from the lamina compacted, and allowed intermingling between, A/B compartments. These findings reveal the diverse conformations of early embryonic chromosomes and uncover a previously unappreciated role for the lamina in systemic chromosome stretching.
Asunto(s)
Caenorhabditis elegans/genética , Cromosomas/química , Lámina Nuclear/fisiología , Animales , Caenorhabditis elegans/embriología , Cromosomas/ultraestructura , Embrión no Mamífero/ultraestructura , Gastrulación/genética , Hibridación Fluorescente in Situ , Conformación MolecularRESUMEN
The complexity of the brain is closely tied to its nature as a genetic mosaic, wherein each cell is distinguished by a unique constellation of somatic variants that contribute to functional and phenotypic diversity. Postzygotic variation arising during neurogenesis is recognized as a key contributor to brain mosaicism; however, recent advances have broadened our understanding to include sources of neural genomic diversity that develop throughout the entire lifespan, from embryogenesis through aging. Moving beyond the traditional confines of neurodevelopment, in this review, we delve into the complex mechanisms that enable various origins of brain mosaicism.
RESUMEN
Maternal mRNAs accumulate during egg growth and must be judiciously degraded or translated to ensure successful development of mammalian embryos. In this review we integrate recent investigations into pathways controlling rapid degradation of maternal mRNAs during the maternal-to-zygotic transition. Degradation is not indiscriminate, and some mRNAs are selectively protected and rapidly translated after fertilization for reprogramming the zygotic genome during early embryogenesis. Oocyte specific cofactors and pathways have been illustrated to control different futures of maternal mRNAs. We discuss mechanisms that control the fate of maternal mRNAs during late oogenesis and after fertilization. Issues to be resolved in current maternal mRNA research are described, and future research directions are proposed.